CN111936493A - High-selectivity FGFRi inhibitor and preparation method and application thereof - Google Patents

Abstract

A high-selectivity FGFR I inhibitor with a structure shown as a formula (I) and a preparation method and application thereof, wherein the definition of each substituent is described in the specification and the claims. The compound can be widely applied to the preparation of medicines for treating tumors, cancers, myeloproliferative diseases, bone or cartilage cell disorder and hypophosphatemia, and is expected to be developed into a new-generation FGFR i inhibitor medicine.

Description

High-selectivity FGFR i inhibitor and preparation method and application thereof Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a high-selectivity FGFR i inhibitor, and a preparation method and application thereof.

Technical Field

Fibroblast Growth Factor Receptors (FGFR) are tyrosine kinase receptors that bind to fibroblast growth factor ligands. There are currently 4 FGFR receptors that have been found to be capable of binding ligands and are closely related in a variety of physiological processes including tissue differentiation, angiogenesis, wound healing, and metabolic regulation. When the ligand binds, the receptor dimerizes and phosphorylates, stimulating activation of protein kinase activity, and recruits many intracellular proteins to bind. These protein interactions can help to activate a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, signaling pathways important to cell growth, proliferation, and survival.

Aberrant activation of this signaling pathway, such as overexpression of FGF ligands or activation mutations through FGFRs, can lead to tumor growth, progression and resistance to traditional cancer therapies. In human tumors, changes in genes that can bring about ligand-independent receptor activation, including gene amplification, chromosomal translocation, and somatic mutation, among others, have been described. While DNA sequencing of thousands of tumor samples in large batches has revealed that components in the FGFR signaling pathway are genes that are highly mutated in human cancers. For example, somatic mutations in FGFR1 have been found in gliomas and lung cancers, mutations in FGFR2 are found in gastric and endometrial cancers, mutations in FGFR3 are found in bladder cancer and multiple myeloma, and mutations in FGFG4 are found in primary rhabdomyosarcoma.

FGF/FGFR-associated tumor types include, but are not limited to, cancer (such as bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer); hematological malignancies (such as multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, myeloproliferative tumors, and fahrenheit macroglobulinemia) and other tumors (such as glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in tumors, FGFR activation has also been found to be associated with skeletal and chondrocyte pathologies, such as achondroplasia and craniosynostosis.

Although some FGFR inhibitors have already entered clinical and preclinical development, they usually have poor selectivity and inhibitory effect on other kinases such as c-kit and PDGFRa, which raises concerns that the therapeutic window is not large enough. Therefore, the development of inhibitors that target FGFR selectivity would be of great interest in the clinical treatment of diseases with elevated FGF or FGFR activity.

Disclosure of Invention

The purpose of the present invention is to provide an FGFR2 and/or FGFR3 inhibitor.

In a first aspect, the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:

wherein X is selected from C (R)₇) OrN；

R ₁Is selected from C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl or-NR₈R ₉Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _{0- 8}-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

R ₂selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_{3- 10}Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _{0- 8}-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

R ₃、R ₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroarylRadical, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _{0- 8}-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _{0- 8}-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

R ₇selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_{3- 10}Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_{1- 10}Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _{0- 8}-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

R ₈、R ₉each independently selected from deuterium, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _0-8-C(O)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-NR₁₃R ₁₄Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _{0- 8}-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Is substituted with a substituent of (A), or, R₈、R ₉Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted by one or more groups selected from the above groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

each R₁₀Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄The above groups are optionally further selected by one or moreFrom deuterium, halogen, hydroxy, carbonyl, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Substituted with the substituent(s);

each R₁₁Selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl or 5-10 membered heteroaryl, optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Substituted with the substituent(s);

each R₁₂Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Substituted with the substituent(s);

each R ₁₃、R ₁₄Each independently selected from hydrogen, deuterium, hydroxy, C_1-10Alkoxy radical, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_{2- 10}Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino or C_1-10Alkanoyl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

or, R₁₃、R ₁₄Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

each r is independently 0, 1 or 2.

Preferably, in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof, X is selected from C (R)₇) Or N; r₇Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _{0- 4}-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄And r is as described for compounds of formula (I).

As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from C (R)₇) Or N; r₇Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetylamino; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.

As a still further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from C (R)₇) Or N; r₇Selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, aziridinyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trithio-methyl, difluoromethyl, dideuteromethyl, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetamido.

As a preferred embodiment, the compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereofIn the salt R₅、R ₆Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄And r is as described for compounds of formula (I).

As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof₅、R ₆Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetamido; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.

As a preferred embodiment, R in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof₃、R ₄Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_2-4Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-8Aryl radical, C_5-8Aryloxy, 5-8 membered heteroaryl or 5-8 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_{3- 8}Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄And r is as described for compounds of formula (I).

As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof₃、R ₄Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_1-4Alkoxy, allyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, phenyl, triazole or triazole; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.

As a preferred embodiment, R in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof₂Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _{0- 4}-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_{5- 8}Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _{0- 4}-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄And r is as described for compounds of formula (I).

As a further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof₂Selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-4-O-R ₁₁、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _{0- 4}-C(O)OR ₁₁or-C_0-4-NR ₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy or carboxylSubstituted, R₁₁、R ₁₂、R ₁₃、R ₁₄And r is as described for compounds of formula (I).

As a preferred embodiment, R in the compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt thereof₁Is selected from C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl or-NR₈R ₉Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、 -C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_{1- 10}Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₈、R ₉、R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄And r is as described for compounds of formula (I).

As a further preferred embodiment, the compound of formula (I) in the compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof has the following structure of formula (iia):

wherein the content of the first and second substances,

ring A is selected from 3-8 membered heterocyclic group, C_5-8Aryl or 5-8 membered heteroaryl;

R ₂selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁or-NR₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, methyl, ethyl, isopropyl,ethoxy, isopropoxy or carboxyl;

R ₃、R ₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclyl or 3-6 membered heterocyclyloxy, said groups optionally being further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, methoxy, ethoxy or isopropoxy, said groups optionally being further substituted by one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

R ₁₅selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_{3- 8}Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azideBase, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、 -C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

m is 0, 1,2 or 3;

R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄and r is as described for compounds of formula (I).

As a still further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, wherein ring a is selected from 4-8 membered heterocyclyl containing 1 or 2 nitrogen heteroatoms, phenyl or 5-6 membered heteroaryl containing 1,2 or 3 nitrogen heteroatoms, preferably, the 5-6 membered nitrogen containing heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3, 5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl or triazolyl;

R ₁₅selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁、-C(O)R ₁₂、-O-C(O)R ₁₂or-C (O) NR₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁、-C(O)R ₁₂、-O-C(O)R ₁₂、-NR ₁₃R ₁₄or-C (O) NR₁₃R ₁₄Substituted with the substituent(s);

m is 0, 1 or 2;

R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄and r is as described for compounds of formula (I).

As a still further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, has the following formula (iiia)₁) Structure, formula (IIIa)₂) Structure (IIIa) or formula (IIIa)₃) The structure is as follows:

wherein the content of the first and second substances,

each R₂Each independently selected from phenyl, 5-6 membered heteroaryl containing 1 or 2 nitrogen heteroatoms or-NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, carboxy, amino, dimethylamino, or diethylamino, optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, cyclopropyl, or hydroxy;

R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, methyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy or isopropoxy, said groups optionally being further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

R _15a、R _15b、R _15c、R _15d、R _15e、R _15feach independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, hydroxy, methoxy, ethoxy, carboxy, methylaminoacyl, ethylaminoacyl or cyclopropylaminoacyl, optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, cyclopropyl, cyclobutyl, cyclohexyl, morpholinyl, piperazinyl, methanesulfonyl, hydroxy, methoxy, carboxy or acetyl;

R ₁₃、R ₁₄each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, amino, dimethylamino, diethylamino or C_1-4Substituted with a substituent of alkanoyl or,

R ₁₃、R ₁₄together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, morpholinyl, piperazinyl, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

each of said heterocyclic groups independently optionally contains 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.

As a still further preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs or a pharmaceutically acceptable salt thereof, has the structure of formula (lib) as follows:

wherein the content of the first and second substances,

R ₂selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl or-NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁or-NR₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

R ₃、R ₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclyl or 3-6 membered heterocyclyloxy, said groups optionally being further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

R ₅、R ₆each is independentIs selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, methoxy, ethoxy or isopropoxy, said groups optionally being further substituted by one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

R ₈、R ₉each independently selected from deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O) _rR ₁₀or-C_0-4-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted with a substituent of (A), or, R₈、R ₉Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted by one or more groups selected from the above groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄and r is as described for compounds of formula (I).

As a still further preferred embodiment, R in said compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof₈、R ₉Each independently selected from deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -O-R₁₁、-C(O)R ₁₂、-O-C(O)R ₁₂or-NR₁₃R ₁₄Is substituted with a substituent of (A), or, R₈、R ₉Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, said group being optionally further substituted by one or more groups selected from the group consisting of_1-4Alkyl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁or-C (O) R₁₂Substituted with the substituent(s);

R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄and r is as described for compounds of formula (I).

As a still further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug, or a pharmaceutically acceptable salt thereof, has the structure of formula (iiib) as follows:

wherein the content of the first and second substances,

R ₂selected from phenyl, 5-6 membered heteroaryl containing 1 or 2 nitrogen heteroatoms or-NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, carboxy, amino, dimethylamino, or diethylamino, optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, cyclopropyl, or hydroxy;

R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, methyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy or isopropoxy, said groups optionally being further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

R ₈、R ₉each independently selected from deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, ═ O, amino, dimethylamino, diethylamino or C_1-4Substituted with a substituent of alkanoyl or,

R ₈、R ₉together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, methoxy, ethoxy, isopropoxy or C_1-4Substituted by alkanoyl group;

R ₁₃、R ₁₄each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, amino, dimethylamino, diethylamino or C_1-4Substituted with a substituent of alkanoyl or,

R ₁₃、R ₁₄together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, morpholinyl, piperazinyl, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

each of said heterocyclic groups independently optionally contains 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.

As a most preferred embodiment, the compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof include, but are not limited to, the following compounds:

in a second aspect, the present invention provides a process for the preparation of a compound of formula (I) as hereinbefore defined, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, comprising the steps of:

alternatively, the first and second electrodes may be,

alternatively, the first and second electrodes may be,

alternatively, the first and second electrodes may be,

wherein, X, R₁、R ₂、R ₃、R ₄、R ₅、R ₆As described for compounds of formula (I).

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described above, a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a fourth aspect, the present invention provides a use of the compound of formula (I), its stereoisomer, prodrug or its pharmaceutically acceptable salt in the preparation of a medicament for treating tumor or cancer.

Preferably, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelocytic leukemia, hodgkin lymphoma or non-hodgkin lymphoma, fahrenheit macroglobulinemia, hairy lymphoma, cellular lymphoma, burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.

In a fifth aspect, the present invention provides a use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating myeloproliferative diseases, bone or cartilage cell disorders, and hypophosphatemia.

Preferably, the myeloproliferative disease is selected from the group consisting of polycythemia, primary thrombocythemia, or primary myelofibrosis; said skeletal or chondrocyte disorder is selected from dysplasia, achondroplasia, dwarfism, lethal Teratocarcinosis (TD), Alpeller's syndrome, Kluyverson's syndrome, Jackson-Weiss syndrome, Beare-Stevenson dermatofret syndrome, Pfeiffer syndrome or cranial muscle atrophy syndrome; the hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or ovarian malacia induced by tumors.

In a sixth aspect, the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, as hereinbefore defined for use as an FGFR inhibitor in the treatment of a disease associated with aberrant expression, mutation or aberrant expression and activity of the respective ligand of an FGFR receptor; preferably, they are useful as selective FGFR2 and/or FGFR3 inhibitors for the treatment of diseases associated with aberrant expression, mutation or aberrant expression and activity of FGFR2 or FGFR3 receptors.

Detailed Description

The inventors of the present application have extensively and intensively studied and, for the first time, developed a highly selective FGFRi inhibitor having the structure of formula (I), the definition of each substituent being as described in the specification and claims, and the preparation method and use thereof. The series of compounds can be widely applied to preparing medicines for treating tumors, cancers, myeloproliferative diseases, bone or cartilage cell disorder and hypophosphatemia, and are expected to be developed into a new generation of FGFRi inhibitor medicines. On the basis of this, the present invention has been completed.

Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group, e.g., "C_1-10Alkyl "refers to straight chain alkyl groups and branched chain alkyl groups containing 1 to 10 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, 2-methylpentyl, 2-dimethylbutyl, and the like, N-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.

Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, e.g., "C_3-10Cycloalkyl "refers to cycloalkyl groups comprising 3 to 10 carbon atoms, divided into monocyclic cycloalkyl, polycyclic cycloalkyl groups, wherein:

monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups which share a carbon atom (referred to as a spiro atom) between single rings, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, di-or multi-spirocycloalkyl depending on the number of spiro atoms shared between rings, including but not limited to:

"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a completely conjugated pi-electron system. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyls depending on the number of constituent rings, including, but not limited to:

"bridged cycloalkyl" refers to all-carbon polycyclic groups in which any two rings share two carbon atoms not directly attached, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. Depending on the number of constituent rings, bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups may be included, including but not limited to:

the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groupsSelected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _{0- 8}-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O)_r(wherein r is an integer 0, 1, 2) but does not include the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. For example, "5-10 membered heterocyclyl" refers to a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclyl" refers to a cyclic group containing 3 to 10 ring atoms.

Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups in which one atom (referred to as a spiro atom) is shared between monocyclic rings, and in which one or more (preferably 1,2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of themRings have a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group, or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. Spiroheterocyclyl groups include, but are not limited to:

"fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more (preferably 1,2, 3 or 4) rings may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O)_r(wherein r is an integer of 0, 1 or 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, but not limited to:

"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms not directly attached, which may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O)_r(wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, depending on the number of constituent rings, including but not limited to:

the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, including but not limited to:

the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _{0- 8}-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, e.g., "C_5-10Aryl "refers to an all-carbon aryl group having 5 to 10 carbons, and" 5-10 membered aryl "refers to an all-carbon aryl group having 5 to 10 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the bond to the parent structureThe rings linked together are aryl rings including, but not limited to:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1,2, 3, or 4) heteroatoms including nitrogen, oxygen, and S (O) r (where r is an integer of 0, 1, 2), e.g., 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, including, but not limited to:

heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _{0- 8}-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., C_{2- 10}Alkenyl means a straight or branched chain alkenyl group having 2 to 10 carbons. Including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azideBase, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, e.g., C_2-10Alkynyl refers to straight or branched chain alkynyl groups containing 2-10 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.

Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above, e.g., "C_1-10Alkoxy "refers to an alkyloxy group having 1 to 10 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.

Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _{0- 8}-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"Cycloalkoxy" means and-O- (unsubstituted cycloalkyl) wherein cycloalkyl is as defined above, e.g., "C _3-10Cycloalkoxy "refers to cycloalkyloxy groups containing 3-10 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

Cycloalkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_{5- 10}Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"3-10 membered heterocyclyloxy" means and-O- (unsubstituted 3-10 membered heterocyclyl), wherein 3-10 membered heterocyclyl is as defined above, 3-10 membered heterocyclyloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

“C _5-10Aryloxy means and-O- (unsubstituted C)_5-10Aryl) in which C_5-10Aryl is as defined above, C_5-10Aryloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

"5-10 membered heteroaryloxy" means and-O- (unsubstituted 5-10 membered heteroaryl), wherein 5-10 membered heteroaryl is as defined above, and 5-10 membered heteroaryloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s).

“C _1-8Alkanoyl "means C_1-8The monovalent radical remaining after removal of the hydroxyl group from the alkyl acid, also commonly referred to as "C_0-7-C (O) - ", e.g." C₁-c (o) — "means acetyl; "C₂-c (o) — "refers to propionyl; "C₃-C (O) -means butyryl or isobutyryl.

“-C _0-8-S(O) _rR ₁₀"means-S (O)_rR ₁₀With sulfur atoms bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-O-R ₁₁"means-O-R₁₁In which the oxygen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-C(O)OR ₁₁"means-C (O) OR₁₁Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-C(O)R ₁₂"means-C (O) R₁₂Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-O-C(O)R ₁₂"means-O-C (O) R₁₂In which the oxygen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_{1- 8}The alkyl group is as defined above.

“-C _0-8-NR ₁₃R ₁₄"means-NR₁₃R ₁₄In which the nitrogen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-C(＝NR ₁₃)R ₁₂"means-C (═ NR)₁₃)R ₁₂Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂"means-N (R)₁₃)-C(＝NR ₁₄)R ₁₂Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-C(O)NR ₁₃R ₁₄"means-C (O) NR₁₃R ₁₄Wherein the carbonyl group is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

“-C _0-8-N(R ₁₄)-C(O)R ₁₃"means-N (R)₁₄)-C(O)R ₁₃In which the nitrogen atom is bound to C_0-8On the alkyl radical, wherein C₀Alkyl means a bond, C_1-8The alkyl group is as defined above.

"halogen substituted C_1-10Alkyl "refers to a 1-10 carbon alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for the hydrogen on the alkyl, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen substituted C_1-10Alkoxy "a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"halogen" means fluorine, chlorine, bromine or iodine. "MeOH" refers to methanol. "DMF" refers to N, N-dimethylformamide. "DCE" refers to 1, 2-dichloroethane. "THF" refers to tetrahydrofuran. "PE" refers to petroleum ether. "EA/EtOAc" refers to ethyl acetate. "DCM" means dichloromethane. "LiOH" refers to lithium hydroxide. "NaOH" refers to sodium hydroxide. "NaNO₂"refers to sodium nitrite. "CuI" refers to cuprous iodide. "Na₂SO ₄"means sodium sulfate. "HOAc" refers to acetic acid. "NH₄OAc "refers to ammonium acetate. "Et₃N "refers to triethylamine. "NH₄Cl "refers to ammonium chloride. "TFA" refers to trifluoroacetic acid. "m-CPBA" refers to m-chloroperoxybenzoic acid. "Pd (PPh)₃) ₄"refers to tetrakis (triphenylphosphine) palladium. "Pd (PPh)₃) ₂Cl ₂"" means "bis-triphenylphosphine palladium dichloride.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated bonds (e.g., olefins).

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts () are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

The LC-MS was measured using an Agilent 6120 mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees centigrade (deg.C).

Preparation of intermediate

1. Preparation of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

The first step is as follows: synthesis of 2, 4-difluoro-3-iodo-1, 5-dimethoxybenzene

The compound 2, 6-difluoro-3, 5-dimethoxyaniline (27.0g, 143mmol) was added to 6.0M hydrochloric acid solution (240mL), NaNO was slowly added dropwise under cooling in an ice-water bath₂Aqueous solution (10.35g, 150mmol, 30mL water). The addition was completed in 25 minutes and the reaction was continued for 15 minutes to yield an orange suspension which was added to aqueous KI solution (94.9g, 570mmol, 150mL of water). The reaction was allowed to warm to room temperature and stirred for 30 minutes to precipitate a solid. Filtering and washing to obtain a crude product. The crude product was added to MeOH (60mL) and stirred at room temperature for 30 min. Filtering, drying to obtain 2, 4-difluoro-3-iodo-1, 5-dimethoxybenzene (2)9.3g, yield: 68%).

¹H NMR(400MHz,DMSO-d ₆)6.69(t,J＝8.0Hz,1H),3.88(s,6H)。

The second step is that: synthesis of (2, 6-difluoro-3, 5-dimethoxyphenylacetylene) yltrimethylsilane

2, 4-difluoro-3-iodo-1, 5-dimethoxybenzene (25.8g, 86.0mmol), trimethylsilylacetylene (36.5mL, 258mmol), CuI (817mg, 4.3mmol), and triethylamine (35.8mL, 258mmol) were added to DMF (250 mL). Pumping gas, protecting with nitrogen, and adding Pd (PPh)₃) ₂Cl ₂(3.15g, 4.3 mmol). Heating at 50 deg.c for 2 hr. The reaction is completed, saturated NH is added₄The solution was quenched with aqueous Cl and extracted 3 times with dichloromethane. The organic phases were combined, Na₂SO ₄And (5) drying. Filtration and concentration gave a crude product (27.0g) which was used directly in the next reaction.

¹H NMR(400MHz,CDCl ₃)6.61(t,J＝8.0Hz,1H),3.86(s,6H),0.28(s,9H)。

The third step: synthesis of 3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene

(2, 6-difluoro-3, 5-dimethoxyphenylacetylene) yltrimethylsilane (27.0g, crude) was added THF/MeOH (200/200mL), followed by aqueous NaOH (8.6mL, 8.6mmol, 1.0N). Stir at room temperature for 15 minutes. The reaction is completed, saturated NH is added₄The solution was quenched with aqueous Cl and extracted 3 times with dichloromethane. The organic phases were combined and anhydrous Na₂SO ₄And (5) drying. Filtered, concentrated, and the crude product slurried with MeOH (50mL) and stirred at room temperature for 30 min. Filtering to obtain 3-ethynyl-2, 4-difluoro-1, 5-dimethoxyPhenyl (15.0g, yield in 2 steps: 88%).

¹H NMR(400MHz,CDCl ₃)6.66(t,J＝8.0Hz,1H),3.88(s,6H),3.52(s,1H)。

The fourth step: synthesis of methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate

3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene (10.0g, 50.5mmol) and methyl 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylate (13.0g, 49.5mmol) were dissolved in DMF (100mL) and CuI (479mg, 2.52mmol), Pd (PPh) and added₃) ₄(2.91g, 2.52mmol) and Et₃N (35.0mL, 252.5mmol), nitrogen blanket. Heating to 100 ℃ and reacting for 1.5 hours. The reaction is completed, cooled to room temperature, and saturated NH is added₄The solution was quenched with aqueous Cl and extracted 3 times with dichloromethane. The organic phases were combined and anhydrous Na₂SO ₄Drying, filtering and concentrating. The crude product was isolated by silica gel column chromatography (PE: EA: DCM ═ 10:2:1) to give methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate (15.4g, yield: 82%).

¹H NMR(400MHz,CDCl ₃)8.82(s,1H),6.69(t,J＝8.0Hz,1H),4.03(s,3H),3.90(s,6H),2.63(s,3H)。

The fifth step: synthesis of 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid

Methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate (30.0g, 78.9mmol) was dissolved in THF (300mL) and LiOH/H added₂O (236.8mL, 236.8mmol, 1M). The reaction was stirred at room temperature for 2 hours. After the reaction is finishedThe whole was concentrated to remove THF, and acidified with dilute hydrochloric acid to pH 3 to precipitate a solid. Filtration, washing with water, and drying gave 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (28.5g, yield: 99%).

¹H NMR(400MHz,DMSO-d ₆)8.98(s,1H),7.15(t,J＝8.0Hz,1H),3.90(s,6H),2.59(s,3H)。

And a sixth step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d ] pyrimidin-8-one

5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (2.5g, 6.83mmol) was dissolved in DCE (50mL) and TFA (0.5mL) and copper acetate (68mg, 0.34mmol) were added. The mixture was heated to reflux and reacted overnight. The reaction was complete, concentrated, slurried with additional MeOH (50mL) and stirred at room temperature for 30 min. Filtration and washing of the solid with MeOH (10mL) dried to give 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d ] pyrimidin-8-one (2.0g, yield: 80%).

¹H NMR(400MHz,DMSO-d ₆)9.23(s,1H),7.22(t,J＝8.4Hz,1H),7.17(s,1H),3.93(s,6H),2.63(s,3H)。

The seventh step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8 (7H) -one

6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d]Pyrimidin-8-one (4.5g, 12.3mmol) was dissolved in HOAc (45mL) and NH was added₄OAc (9.4g, 123mmol), and the reaction was stirred at 120 ℃ overnight. Cooling at room temperature, adding a proper amount of water (30mL), stirring, performing suction filtration, washing a filter cake with water (20mL), and drying to obtain 6- (2, 6-difluoro-3, 5-Dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidin-8 (7H) -one (4.22g, yield: 94%).

¹H NMR(400MHz,DMSO-d ₆)12.28(s,1H),9.24(s,1H),7.17(t,J＝8.4Hz,1H),6.76(s,1H),3.92(s,6H),2.63(s,3H)。

Eighth step: synthesis of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8 (7H) -one (1g,2.74mmol) was dissolved in DCE (80mL), heated to 90 degrees, then phenylphosphonyl dichloride (3.0mL, 21.92mmol) was added, heated and stirred for 16 hours, cooled, the pH was adjusted to neutral under ice bath, DCM was extracted, and silica gel column chromatography (DCM/EtOAc ═ 0-10%) was performed to isolate 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine (930mg, 88% yield).

¹H NMR(400MHz,CDCl ₃)9.25(s,1H),7.78(t,J＝1.2Hz,1H),6.75(t,J＝8.0Hz,1H),3.93(s,6H),2.77(s,3H)。MS m/z(ESI):384[M+H] ⁺。

2. Preparation of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine

8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine (930mg, 2.42mmol) was dissolved in DCM (50mL), and m-CPBA (1.23g, 6.05mmol) was added and stirred at room temperature for 2 hours. The reaction was complete, quenched with sodium thiosulfate, extracted with DCM and isolated by silica gel column chromatography (DCM/EtOAc 0-35%) to give 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine (800mg, 79% yield).

¹H NMR(400MHz,CDCl ₃)9.76(s,1H),8.03(t,J＝1.2Hz,1H),6.80(t,J＝8.0Hz,1H),3.95(s,6H),3.58(s,3H)。MS m/z(ESI):416[M+H] ⁺。

3. Preparation of 8-chloro-6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

The first step is as follows: synthesis of methyl 5- ((3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate

Methyl 5-bromo-2- (methylthio) pyrimidine-4-carboxylate (2631mg, 10.0mmol), 1-ethynyl-3, 5-dimethoxybenzene (1622mg, 10.0mmol) were dissolved in dry THF (50mL), purged with air and protected with nitrogen. Et was then added sequentially₃N(2.8mL，20.0mmol)，Pd(PPh ₃) ₂Cl ₂(702mg，1.0mmol)，PPh ₃(525mg, 2.0mmol) and CuI (190 mg,1.0 mmol). The reaction was stirred overnight at 90 ℃. The reaction was completed, cooled to room temperature, and saturated NaHCO was added₃Aqueous (100mL), EtOAc (100mL) was extracted 2 times. Washed with saturated brine and anhydrous Na₂SO ₄And (5) drying. Filtration, concentration and silica gel column chromatography (PE: EA4:1) gave methyl 5- ((3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate (2.5g, yield: 73%). MS M/z (ESI) 345.2[ M + H ]] ⁺。

The second step is that: synthesis of 5- ((3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid

Methyl 5- ((3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate (600mg, 1.742mmol) was dissolved in methanol (15mL) and a solution of lithium hydroxide monohydrate (366mg, 8.711mmol) in water (5mL) was added. The reaction was stirred at room temperature overnight and was complete. The organic solvent was removed by evaporation under reduced pressure, EtOAc (30mL) was added to the aqueous phase, and the pH was adjusted to 3-4 with 1N hydrochloric acid solution. The organic phase was separated, washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration gave 5- ((3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid, which was used directly in the next reaction. MS M/z (ESI) 331.2[ M + H] ⁺。

The third step: synthesis of 6- (3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d ] pyrimidin-8-one

Acetone (25mL) was added to 5- ((3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (584mg,1.768mmol), and AgNO was added to the suspension₃(180mg,1.059 mmol). The reaction was stirred at room temperature for 4 hours and a green solid precipitated. Filtering to obtain 6- (3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d]Pyrimidin-8-one (600mg, crude). MS M/z (ESI) 331.2[ M + H] ⁺。

The fourth step: synthesis of 6- (3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8 (7H) -one

6- (3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d]Pyrimidin-8-one (600mg, crude) was added glacial acetic acid (50mL) and ammonium acetate (2.1g, 27.243mmol) was added. The reaction was heated to 115 ℃ for 16 hours. The reaction was completed, cooled to room temperature, and saturated aqueous sodium bicarbonate solution was slowly poured in. EtOAc (100mL) extraction. Organic compoundsThe phase separated liquid is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (eluent: CH)₂Cl ₂0-6% MeOH) to obtain 6- (3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3, 4-d)]Pyrimidin-8 (7H) -one (298mg, two-step yield: 50%). MS M/z (ESI) 330.2[ M + H] ⁺。

The fifth step: synthesis of 8-chloro-6- (3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

6- (3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidin-8 (7H) -one (200mg, 0.61mmol) and N, N-diisopropylethylamine (780mg, 6.1mmol) were added to acetonitrile (10mL), POCl was added₃(4 mL). The reaction was stirred overnight at 90 ℃. The solvent was removed by evaporation under reduced pressure. EtOAc (10mL) was added for dilution and washing with saturated sodium bicarbonate solution. The organic phase was separated, washed with saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating, and separating by column chromatography (eluent: PE/EtOAc 0-40%) to obtain 8-chloro-6- (3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (60mg, yield: 28%). MS M/z (ESI) 348.2[ M + H] ⁺。

And a sixth step: synthesis of 8-chloro-6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

Compound 8-chloro-6- (3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (920mg,2.65mmol) was dissolved in dichloromethane (32mL), purged with nitrogen three times and the reaction cooled to-40 ℃. Dropwise adding SO₂Cl ₂A solution (0.64mL, 8.0mmol) in dichloromethane (4mL) was reacted at 40 ℃ for 2.5 hours. Adding saturated NaHCO₃Aqueous solution (50mL) was quenched and stirred at room temperatureFor 1 hour, separating, extracting the aqueous phase with dichloromethane (50mL), combining the organic phases, washing twice with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain 8-chloro-6- (2, 6-dichloro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3, 4-d%]Pyrimidine (1.02g, yield: 98%). MS (ESI) M/z 416.2 and 418.2[ M +1 ]] ⁺。

4. Preparation of (6- (2-cyanopropan-2-yl) pyridin-3-yl) boronic acid

The first step is as follows: synthesis of 2- (5-bromopyridin-2-yl) -2-methylpropanenitrile

To a solution of 2- (5-bromopyridin-2-yl) acetonitrile (300mg,1.523mmol), potassium tert-butoxide (427mg,3.808mmol) and 18-crown-6 (60mg,0.228mmol) in tetrahydrofuran (8mL) was added dropwise methyl iodide (1.7g,12.184 mmol). The suspension after the addition was stirred for a further 18 hours. The reaction mixture was diluted with ethyl acetate and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (PE/EtOAc 0-30%) to give 2- (5-bromopyridin-2-yl) -2-methylpropanenitrile (230mg, yield: 67%). MS M/z (ESI) 225.2, 227.2[ M + H] ⁺。

The second step is that: synthesis of 2-methyl-2- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propionitrile

To 2- (5-bromopyridin-2-yl) -2-methylpropanenitrile (230mg,1.022mmol), pinacoline borate (520mg,2.044mmol) and potassium acetate (300mg,3.057mmol) in dioxane (5.5mL) was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (66mg,0.081 mmol). The reaction solution was replaced with nitrogen, and then heated to 80 ℃ and stirred for 20 hours. Concentrating, and separating by column chromatography (PE: EtOAc 0-40%) to obtain 2-methyl-2- (5- (4,4, 5)5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propionitrile (170mg crude). MS M/z (ESI) 273.4[ M + H] ⁺。

The third step: synthesis of (6- (2-cyanopropan-2-yl) pyridin-3-yl) boronic acid

To 2-methyl-2- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl) propionitrile (170mg crude) in methanol (2mL) was added 2N hydrochloric acid (2 mL). The solution was stirred at room temperature for 18 hours. After concentration, water (10mL) was added. Filtration and washing with water gave (6- (2-cyanopropan-2-yl) pyridin-3-yl) boronic acid (80mg, two-step yield: 41%). MS M/z (ESI) 191.2[ M + H] ⁺。

5. Preparation of (1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid

First step, Synthesis of tert-butyl 3- ((methylsulfonyl) oxo) pyrrolidine-1-carboxylate

Tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0g,5.35mmol) and N, N-diisopropylethylamine were dissolved in dichloromethane (20mL), the reaction was cooled to 0 deg.C, and methanesulfonyl chloride (736mg, 6.42mmol) was added dropwise at 0 deg.C. The reaction mixture was reacted at room temperature for 2 hours, diluted with dichloromethane (100mL), washed with saturated sodium bicarbonate (50mL) and ammonium chloride solution (50mL), respectively, and dried over anhydrous sodium sulfate. Filtering, rotary evaporation and concentration to obtain tert-butyl 3- ((methylsulfonyl) oxo) pyrrolidine-1-carboxylate (1.40g, yield: 99%). MS M/z (ESI) 206.2[ M-Bu + H] ⁺。

Second step, synthesis of tert-butyl 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylate

To a solution of tert-butyl 3- ((methanesulfonyl) oxo) pyrrolidine-1-carboxylate (1.40g, 5.28mmol) and 4-pyrazole boronic acid pinacol ester (683mg, 3.52mmol) in acetonitrile (10mL) was added cesium carbonate (1.72g, 5.28 mmol). The reaction mixture was reacted at 100 ℃ for 17 hours. Cooled, diluted with water (100mL), extracted with ethyl acetate (60mL × 2), washed with saturated brine (50mL), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and column chromatography (DCM: EtOAc ═ 0-30%) were performed to give tert-butyl 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylate (700mg, yield: 55%). MS M/z (ESI) 308.4[ M-Bu + H] ⁺。

Third step Synthesis of (1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid

To a mixed solution of tert-butyl 3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylate (700mg, 1.93mmol of acetonitrile (30mL) and water (10mL), sodium periodate (2.06g, 9.64mmol) and ammonium acetate (1.51g, 9.64mmol) were added, the reaction solution was allowed to react at room temperature for 17 hours, ethyl acetate (100mL) was added for dilution, dried over anhydrous sodium sulfate was added, filtration was performed, the filtrate was concentrated, and reverse phase column chromatography [ mobile phase (acetonitrile: water ═ 0 to 30%)](1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid (210mg, yield: 39%) was isolated. MS M/z (ESI) 226.2[ M-Bu + H] ⁺。

The intermediate 6-8 is prepared by a synthesis method of the reference intermediate 5:

9. preparation of (6- (methylcarbamoyl) pyridin-3-yl) boronic acid

First step, synthesis of 5-bromo-N-methyl picolinamide

To a solution of 5-bromoo-picolinic acid (1.0g,4.95mmol) and aqueous methylamine (576mg,7.43mmol) in N, N-dimethylformamide (10mL) were added N, N-diisopropylethylamine (3.19g,24.75mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.90g,9.9mmol) and 1-hydroxybenzotriazole (1.34g,9.9 mmol). The reaction solution was stirred at room temperature for 18 hours, diluted with ethyl acetate (150mL), washed with saturated sodium bicarbonate (50mL) and ammonium chloride solution (50mL), respectively, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 5-bromo-N-methylpyridinamide (300mg, yield: 28%). MS M/z (ESI) 215.2,217.2[ M + H ]] ⁺。

Second step synthesis of (6- (methylcarbamoyl) pyridin-3-yl) boronic acid

To a solution of 5-bromo-N-methylpyridinamide (300mg,1.4mmol) and pinacol diboron (533mg,2.1mmol) in 1, 4-dioxane (6mL) was added potassium acetate (342mg,3.5mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (98mg,0.14 mmol). The reaction solution isStirring was carried out at 85 ℃ for 18 hours. Filtering the reaction solution, washing a filter cake with 1, 4-dioxane (5mL), concentrating the filtrate, and performing reverse phase column chromatography [ mobile phase (acetonitrile: water: 0-20%)](6- (methylcarbamoyl) pyridin-3-yl) boronic acid was isolated (170mg, yield: 67%). MS M/z (ESI) 180.2[ M + H] ⁺。

The intermediate 11-12 is prepared by a synthetic method of the reference intermediate 10:

preparation of the example Compounds

Example preparation of 16- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (pyridin-3-yl) pyrido [3,4-d ] pyrimidine

The first step is as follows: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (60mg,0.156mmol) and 2-fluorobenzeneboronic acid (88mg,0.625mol) in dioxane (4mL) was added tetrakis (triphenylphosphine) palladium (18mg,0.016mmol) and 2N aqueous sodium carbonate (0.3 mL). The reaction solution was replaced with nitrogen, and then heated to 90 ℃ and stirred for 18 hours. Concentrating, and separating by direct column chromatography (DCM: EtOAc 0-15%) to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (63mg, yield: 91%). MS M/z (ESI) 444.4[ M + H ]] ⁺。

The second step is that: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (pyridin-3-yl) pyrido [3,4-d ] pyrimidine

In the presence of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (30mg,0.068mmol), 3-pyridylboronic acid (41.6mg,0.338mol), ((thiophene-2-carbonyl) oxo) copper (32mg,0.170mmol) and zinc acetate (25mg,0.136mmol) in dioxane (4mL) was added tetrakis (triphenylphosphine) palladium (7.8mg,0.007 mmol). The reaction solution was replaced with nitrogen, and then heated to 120 ℃ and stirred for 18 hours. After dilution with dichloromethane, washing with saturated ammonium chloride, the organic phase is filtered off of insoluble material, concentrated and isolated as a plate (DCM: MeOH ═ 50:1) yielding 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (2-fluorophenyl) -2- (pyridin-3-yl) pyrido [3,4-d]Pyrimidine (13.7mg, yield: 42%). MS M/z (ESI) 475.4[ M + H ]] ⁺。

¹H NMR(400MHz,CDCl ₃)9.78(s,1H),9.67(s,1H),8.87(d,J＝7.9Hz,1H),8.80(s,1H),8.02(t,J＝1.2Hz,1H),7.81(td,J＝7.3,1.8Hz,1H),7.56(tdd,J＝7.3,5.1,1.8Hz,2H),7.36(td,J＝7.5,1.1Hz,1H),7.33–7.27(m,1H),6.77(t,J＝8.0Hz,1H),3.95(s,6H)。

Examples 2-4 were prepared according to the synthetic method of example 1:

example 54 preparation of (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) morpholine

The first step is as follows: synthesis of 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8-yl) morpholine

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (700mg, 1.83mmol) in acetonitrile (7mL) were added N, N-diisopropylethylamine (472mg, 3.66mmol) and morpholine (800mg, 9.15 mmol). The reaction solution was placed in a sealed tube and reacted at 90 ℃ for 18 hours. After cooling, the mixture was diluted with ethyl acetate (100mL), washed with a saturated ammonium chloride solution (50mL), and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and separating by column chromatography (EA: DCM ═ 0-20%) to obtain 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidin-8-yl) morpholine (700mg, yield: 88%). MS M/z (ESI) 435.4[ M + H] ⁺。

The second step is that: synthesis of 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) morpholine

In the presence of 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidin-8-yl) morpholine (400mg, 0.92mmol) and 1-methyl-1H-pyrazole-4-boronic acid (348mg, 2.76mmol) in tetrahydrofuran (10mL) was added copper (I) 3-methylsalicylate (394mg, 1.84mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (67mg,0.09mmol) and zinc acetate (338mg, 1.84 mmol). The reaction solution was reacted at 120 ℃ for 18 hours. After cooling, the mixture was diluted with ethyl acetate (100mL), washed with a saturated ammonium chloride solution (50mL), and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate, and separating by column chromatography (EA: DCM 0-100%) to obtain 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1-methyl-1H-pyrazol-4-yl) pyrido [3, 4-d)]Pyrimidin-8-yl) morpholine (200mg, yield: 46%). MS m-z(ESI):469.4[M+H] ⁺。

¹H NMR(400MHz,CDCl ₃)9.16(s,1H),8.09(s,1H),8.03(s,1H),7.16(d,J＝1.3Hz,1H),6.62(t,J＝7.9Hz,1H),4.10(t,J＝4.7Hz,4H),3.92(s,3H),3.87(t,J＝4.7Hz,4H),3.84(s,6H)。

Examples 6-43 were prepared according to the synthetic method of example 5:

example preparation of 442- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethylpyrido [3,4-d ] pyrimidin-8-amine

The first step is as follows: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethyl-2- (methylthio) pyrido [3,4-d ] pyrimidin-8-amine

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]An aqueous solution (0.5mL, 40%) of dimethylamine was added to acetonitrile (5mL) containing pyrimidine (120mg,0.313mmol), and the reaction mixture was heated to 105 ℃ in a sealed pot and stirred for 16 hours. Concentrating, diluting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethyl-2- (methylthio) pyrido [3, 4-d%]Pyrimidin-8-amine (109mg, yield: 89%). 393.4[ M + H ] in MS M/z (ESI)] ⁺。

The second step is that: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethyl-2- (methylsulfonyl) pyrido [3,4-d ] pyrimidin-8-amine

8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (109mg, 0.278mmol) was dissolved in DCM (5mL), and m-CPBA (144mg, 0.833mmol) was added and stirred at room temperature for 20 hours. Quenching with sodium thiosulfate, DCM extraction and silica gel column chromatography (DCM/EtOAc 0-15%) to give 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethyl-2- (methylsulfonyl) pyrido [3,4-d]Pyrimidin-8-amine (42mg, yield: 35%). MS M/z (ESI) 425.4[ M + H] ⁺。

The third step: synthesis of 2- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethylpyrido [3,4-d ] pyrimidin-8-amine

6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethyl-2- (methylsulfonyl) pyrido [3,4-d]A solution of pyrimidin-8-amine (20mg,0.047mmol), azetidine hydrochloride (22mg,0.236mmol) and N, N-diisopropylethylamine (48mg,0.376mmol) in dioxane (3mL) was stirred at 100 ℃ for 18 hours. After concentration the crude mixture was directly purified on a plate (PE: EtOAc ═ 3:1) to give 2- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N, N-dimethylpyrido [3,4-d ] N]Pyrimidin-8-amine (15.6mg, yield: 83%). MS M/z (ESI) 402.4[ M + H] ⁺。

¹H NMR(400MHz,CDCl ₃)8.92(s,1H),7.03(s,1H),6.68(t,J＝7.9Hz,1H),4.27(t,J＝7.5Hz,4H),3.91(s,6H),3.46(s,6H),2.44(p,J＝7.5Hz,2H)。

Examples 45-50 were prepared according to the synthetic method of example 44:

example 516- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -2- (pyridin-3-yl) pyrido [3,4-d ] pyrimidine

The first step is as follows: synthesis of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (pyridin-3-yl) pyrido [3,4-d ] pyrimidine

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (100mg,0.260mmol), 3-pyridineboronic acid (95.8mg,0.78mmol), copper (I) 3-methylsalicylate (111.6mg,0.52mmol) and zinc acetate (143.1mg,0.78mmol) in dioxane (3.0mL) was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (19.1mg,0.026 mmol). The reaction solution was replaced with nitrogen, and then heated to 50 ℃ and stirred for 24 hours. After dilution with dichloromethane, washing with saturated ammonium chloride, the organic phase is filtered off of insoluble material, concentrated and isolated as a plate (DCM: MeOH ═ 50:1) yielding 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (pyridin-3-yl) pyrido [3,4-d]Pyrimidine (38.0mg, yield: 35%). MS M/z (ESI) 415.8[ M + H ]] ⁺。

The second step is that: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -2- (pyridin-3-yl) pyrido [3,4-d ] pyrimidine

In the presence of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (pyridin-3-yl) pyrido [3,4-d]After adding diisopropylethylamine (12.2mg,0.095mmol) to a solution of pyrimidine (8.0mg,0.019mmol), 3-methoxy-3-methylcyclobutylamine hydrochloride (10.45mg,0.076mmol) in acetonitrile (2.0ml), sealing, heating to 95 deg.C and stirring for 16 hours, concentrating and isolating the 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -2- (pyridin-3-yl) pyrido [3,4-d ] directly on the preparation plate (DCM: MeOH ═ 50:1)]Pyrimidine (6.8mg, yield: 73.5%). MS M/z (ESI) 480.5[ M + H ]] ⁺。

¹H NMR(400MHz,CDCl ₃)9.71(s,1H),9.32(s,1H),8.79-8.72(m,2H),7.495(dd,J＝8.0Hz,1H),7.07(s,1H),6.71(t,J＝8.0Hz,1H),4.78(m,4H),3.93(s,6H),3.36(s,3H),1.63(s,3H)。

Examples 52-54 were prepared according to the synthetic method of example 51:

example preparation of 554- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) morpholine

The first step is as follows: synthesis of tert-butyl 3- (4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8-morpholinopyrido [3,4-d ] pyrimidin-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylate

In the presence of 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidin-8-yl) morpholine (30mg, 0.07mmol) and (1- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) boronic acid (39mg, 0.14mmol) in tetrahydrofuran (2mL) was added copper (I) 3-methylsalicylate (30mg, 0.14mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (5mg,0.007mmol) and zinc acetate (26mg, 0.14 mmol). The reaction mixture was reacted at 120 ℃ for 18 hours. After cooling, the mixture was diluted with ethyl acetate (60mL), washed with a saturated ammonium chloride solution (20mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate yielded tert-butyl 3- (4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8-morpholinopyrido [3, 4-d) with plate preparation (EA: DCM ═ 4:1)]Pyrimidin-2-yl) -1H-pyrazol-1-yl) pyrrolidines-1-Carboxylic acid ester (25mg, yield: 58%). MS M/z (ESI) 624.6[ M + H ]] ⁺。

¹H NMR(400MHz,CDCl ₃)9.29(s,1H),8.30(s,1H),8.21(s,1H),7.25(s,1H),6.74(t,J＝7.9Hz,1H),5.02–4.95(m,1H),4.29(t,J＝4.2Hz,4H),3.99(t,J＝4.6Hz,4H),3.94(s,6H),3.89–3.77(m,2H),3.71–3.60(m,2H),2.53–2.42(m,2H),1.49(s,9H).

The second step is that: synthesis of 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) morpholine

In tert-butyl 3- (4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8-morpholinopyrido [3, 4-d)]To a solution of pyrimidin-2-yl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylate (23mg, 0.037mmol) in dichloromethane (2mL) was added trifluoroacetic acid (1 mL). The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (30mL), washed with a saturated sodium bicarbonate solution (30mL), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and isolation of the prep. plate (dichloromethane: methanol ═ 10: 1) gave 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d]Pyrimidin-8-yl) morpholine (19mg, yield: 98%). MS M/z (ESI) 524.6[ M + H ]] ⁺。

¹H NMR(400MHz,CDCl ₃)9.18(s,1H),8.16(s,2H),7.25(s,1H),6.64(s,1H),5.03(s,1H),4.12(s,4H),3.88(br s,10H),3.64(s,2H),3.58(s,2H),2.51(s,1H),2.35(s,1H)。

The third step: synthesis of 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-8-yl) morpholine

In the presence of 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1- (pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d]Trifluoromethanesulfonyl chloride (8mg,0.065mmol) in a solution of pyrimidin-8-yl) morpholine (17mg, 0.033mmol) and N, N-diisopropylethylamine (13mg,0.098mmol) in dichloromethane (2 mL). The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane (30mL), washed with a saturated ammonium chloride solution (20mL), and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate and isolation of the prep. plate (dichloromethane: ethyl acetate ═ 1: 1) gave 4- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (1- (1- (methylsulfonyl) pyrrolidin-3-yl) -1H-pyrazol-4-yl) pyrido [3,4-d]Pyrimidin-8-yl) morpholine (11mg, yield: 59%). MS M/z (ESI) 602.6[ M + H ]] ⁺。

¹H NMR(400MHz,CDCl ₃)9.26(s,1H),8.24(s,1H),8.21(s,1H),7.26–7.25(m,1H),6.72(t,J＝7.9Hz,1H),5.07–4.99(m,1H),4.23–4.13(m,4H),3.98–3.94(m,4H),3.94(s,6H),3.92–3.83(m,2H),3.71–3.63(m,2H),2.93(s,3H),2.57–2.49(m,2H)。

Examples 56-60 were prepared according to the synthetic method of example 55:

biological test evaluation

First, FGFR 1-2 biochemical kinase analysis in vitro

The invention adopts Caliper Assay to determine the characteristics of the compounds on the inhibitory activity of FGFR1 and FGFR 2. The specific experimental process is as follows:

1. the kinase reaction carried out by the present invention was carried out in a 384-well plate by incubating the reaction system with a certain concentration of kinase (Carna), a certain concentration of ATP and 1. mu.M of peptide FAM-P22(GL Biochem, Cat. No.112393)) at 28 ℃ for a certain period of time in a reaction system of 50mM HEPES, pH7.5, 0.0015% Brij-35 and a basic kinase buffer; for FGFR1, the enzyme concentration was 0.25nM, the ATP concentration was 382 μ M, and the reaction time was 20 minutes; for FGFR2, the enzyme concentration was 2.5nM, the ATP concentration was 1 μ M, and the reaction time was 40 minutes;

2. the reaction was stopped by adding a stop solution (100mM HEPES, pH7.5, 0.2% Caliper coating reagent, 50mM EDTA and 0.015% Brij 35);

3. transferring the hole plate with the stopped kinase reaction to a Caliper to read data;

4. the phosphorylated and unphosphorylated peptides were separated using Caliper microfluidic migration shift technology and the analyte was transferred by constant buffer flow through the chip and the migration of the substrate peptide was monitored by its labeled fluorescent signal. Kinase activity was calculated using the amount of phosphopeptide formed.

5. Determination of IC by analysis of percent inhibition by non-Linear regression at different Compound concentrations₅₀The value is obtained. The enzymatic activities of the compounds of the specific examples are shown in Table 1.

TABLE 1 results of the enzymatic Activity measurements and their Selectivity

Second, Cell Titer Glo (CTG) experiment)

The inhibition of cell proliferation by compounds dependent on the FGFR signaling pathway was evaluated by a survival assay, measured using CTG reagent (Promega, # G7573). Cell lines representing different tumor types, such as H1581 lung cancer cell (with FGFR1 gene amplification) or Snu-16 stomach cancer cell (with FGFR2 gene amplification) from Nanjing Kebai, were selected and the specific experimental procedures were as follows:

1.90 ul of cells were seeded into tissue culture medium-treated 96-well plates (Costar #3904), incubated overnight at 37 ℃ in a 5% carbon dioxide incubator, followed by the addition of 10. mu.L of medium containing 10-fold dilutions of the compound at its final concentration.

2. Dose-effect effects were evaluated by serial dilutions of test compounds, starting at concentrations of 10 μ M or less.

3. Cells were incubated at 37 ℃ with 5% CO₂After 3 days of incubation, 50 μ L of CTG was added and readings were taken using envision (pelkin elmer) to quantify cellular ATP levels the percent inhibition of cell proliferation/survival by the compounds was assessed by comparing cellular ATP levels after the action of different concentrations of inhibitor to cellular ATP levels of DMSO control

4. Four parameter curve fitting in Graphpad Prism was used to determine the concentration of compound that resulted in half maximal growth Inhibition (IC)₅₀). The cellular activities of the compounds of the specific examples are shown in Table 2.

TABLE 2 results of cell Activity assays and Selectivity thereof

From the enzymology or cell activity data of the compounds of the specific embodiments, the compounds of the series have strong inhibitory effect on the kinase activity of FGFR, especially FGFR1 and/or FGFR 2. In addition, the experimental results show that the series of compounds have very good selectivity on FGFR1, are expected to be developed into a new generation of FGFR inhibitors, particularly high-selectivity FGFR2 inhibitors, and meet the clinical application requirements.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (19)

1. A compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof:

   

   wherein the content of the first and second substances,

   x is selected from C (R)₇) Or N;

   R ₁is selected from C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl or-NR₈R ₉Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

   R ₂selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _{0- 8}-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_{3- 10}Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_{5- 10}Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

   R ₃、R ₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_{5- 10}Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_{1- 10}Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

   R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

   R ₇selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _{0- 8}-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _0-8-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

   R ₈、R ₉each independently selected from deuterium, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-8-S(O) _rR ₁₀、-C _0-8-C(O)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-NR₁₃R ₁₄Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _{0- 8}-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Is substituted with a substituent of (A), or, R₈、R ₉Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted by one or more groups selected from the above groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10CycloalkanesA group, a 3-to 10-membered heterocyclic group, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-8-S(O) _rR ₁₀、-C _0-8-O-R ₁₁、-C _{0- 8}-C(O)OR ₁₁、-C _0-8-C(O)R ₁₂、-C _0-8-O-C(O)R ₁₂、-C _0-8-NR ₁₃R ₁₄、-C _0-8-C(＝NR ₁₃)R ₁₂、-C _0-8-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-8-C(O)NR ₁₃R ₁₄or-C_0-8-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

   each R₁₀Independently selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, hydroxy, carbonyl, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Substituted with the substituent(s);

   each R₁₁Independently selected from hydrogen, deuterium, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_{5- 10}Aryl or 5-to 10-membered heteroaryl, the above groupsOptionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, carbonyl, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Substituted with the substituent(s);

   each R₁₂Selected from hydrogen, deuterium, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or-NR₁₃R ₁₄Substituted with the substituent(s);

   each R₁₃、R ₁₄Each independently selected from hydrogen, deuterium, hydroxy, C_1-10Alkoxy radical, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino or C_1-10Alkanoyl optionally further substituted by oneOr more are selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

   or, R₁₃、R ₁₄Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-10Cycloalkyl radical, C_3-10Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C_5-10Aryl radical, C_5-10Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C_1-10Substituted by alkanoyl group;

   each r is independently 0, 1 or 2.
2. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein X is selected from C (R)₇) Or N; r₇Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_{2- 4}Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4- S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄R is as defined in claim 1;

   preferably, R₇Selected from hydrogen, deuterium, halogen, cyanoNitro, azido, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, oxetanyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetylamino; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino;

   more preferably, R₇Selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, aziridinyl, azacyclohexyl, phenyl, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, trithio-methyl, difluoromethyl, dideuteromethyl, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetamido.
3. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₅、R ₆Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O) _rR ₁₀、-C _{0- 4}-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄R is as defined in claim 1;

   preferably, R₅、R ₆Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl, allyl, ethynyl, C_3-6Cycloalkyl, oxaCyclobutyl, azacyclopentyl, azacyclohexyl, phenyl, triazole, methylsulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl, or acetylamino; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
4. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₃、R ₄Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_{1- 4}Alkoxy radical, C_2-4Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Cycloalkoxy, 3-to 8-membered heterocyclic group, 3-to 8-membered heterocyclic oxy group, C_5-8Aryl radical, C_5-8Aryloxy, 5-8 membered heteroaryl or 5-8 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄R is as defined in claim 1;

   preferably, R₃、R ₄Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C_1-4Alkyl radical, C_1-4Alkoxy, allyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, phenyl, triazole or triazole; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
5. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₂Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _{0- 4}-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_{1- 4}Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _{0- 4}-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄R is as defined in claim 1;

   preferably, R₂Selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, -C_0-4-O-R ₁₁、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _{0- 4}-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁or-C_0-4-NR ₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy or carboxyl, R₁₁、R ₁₂、R ₁₃、R ₁₄R is as defined in claim 1.
6. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein R is₁Is selected from C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl or-NR₈R ₉Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-10Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocyclyl, C_5-10Aryl, 5-10 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted by a substituent of (A), R₈、R ₉、R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄R is as defined in claim 1.
7. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein said compound of formula (I) has the following structure (iia):

   

   wherein ring A is selected from 3-8 membered heterocyclic group, C_5-8Aryl or 5-8 membered heteroaryl;

   R ₂selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl or-NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁or-NR₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

   R ₃、R ₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclyl or 3-6 membered heterocyclyloxy, said groups optionally being further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

   R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, methoxy, ethoxy or isopropoxy, said groups optionally being further substituted by one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

   R ₁₅selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C _0-4-N(R ₁₃)-C(O)R ₁₂Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, halo-substituted C_1-4Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

   m is 0, 1,2 or 3;

   R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄r is as defined in claim 1.
8. A compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that ring a is selected from 4-8 membered heterocyclyl containing 1 or 2 nitrogen heteroatoms, phenyl or 5-6 membered heteroaryl containing 1,2 or 3 nitrogen heteroatoms, preferably the 5-6 membered nitrogen containing heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3, 5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl or triazolyl;

   R ₁₅selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁、-C(O)R ₁₂、-O-C(O)R ₁₂or-C (O) NR₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C_1-4Alkyl, halo-substituted C_1-10Alkyl, deuterium substituted C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁、-C(O)R ₁₂、-O-C(O)R ₁₂、-NR ₁₃R ₁₄or-C (O) NR₁₃R ₁₄Substituted with the substituent(s);

   m is 0, 1 or 2;

   R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄r is as defined in claim 7.
9. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 7, wherein said compound of formula (I) has the following formula (iiia)₁) Structure, formula (IIIa)₂) Structure (IIIa) or formula (IIIa)₃) The structure is as follows:

   

   wherein the content of the first and second substances,

   each R₂Each independently selected from phenyl, 5-6 membered heteroaryl containing 1 or 2 nitrogen heteroatoms or-NR₁₃R ₁₄The above radicals being optionally further substituted by one orPlural is selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, carboxy, amino, dimethylamino, or diethylamino, optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, cyclopropyl, or hydroxy;

   R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, methyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy or isopropoxy, said groups optionally being further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

   R _15a、R _15b、R _15c、R _15d、R _15e、R _15feach independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, hydroxy, methoxy, ethoxy, carboxy, methylaminoacyl, ethylaminoacyl or cyclopropylaminoacyl, optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, cyclopropyl, cyclobutyl, cyclohexyl, morpholinyl, piperazinyl, methanesulfonyl, hydroxy, methoxy, carboxy or acetyl;

   R ₁₃、R ₁₄each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, amino, dimethylamino, diethylamino or C_1-4Substituted with a substituent of alkanoyl or,

   R ₁₃、R ₁₄together with the nitrogen atom to which they are directly attachedTo a 4-to 8-membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuterylmethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, morpholinyl, piperazinyl, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

   each of said heterocyclic groups independently optionally contains 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.
10. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 1, wherein said compound of formula (I) has the following structure (lib):

    

    wherein R is₂Selected from hydrogen, deuterium, halogen, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl or-NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁、-C(O)OR ₁₁or-NR₁₃R ₁₄Optionally further substituted by one or more substituents selected from deuterium, halogen, C_1-4Alkyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, ═ O, hydroxy, methoxy, ethoxy, isopropoxy, or carboxy;

    R ₃、R ₄each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, 3-6 membered heterocyclyl or 3-6 membered heterocyclyloxy; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

    R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, hydroxy, methoxy, ethoxy or isopropoxy; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;

    R ₈、R ₉each independently selected from deuterium, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, -C_0-4-S(O) _rR ₁₀or-C_0-4-C(O)R ₁₂Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Is substituted with a substituent of (A), or, R₈、R ₉Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl group, optionally further substituted by one or more groups selected from the above groups optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_{2- 4}Alkynyl, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -C_0-4-S(O) _rR ₁₀、-C _0-4-O-R ₁₁、-C _0-4-C(O)OR ₁₁、-C _0-4-C(O)R ₁₂、-C _0-4-O-C(O)R ₁₂、-C _0-4-NR ₁₃R ₁₄、-C _0-4-C(＝NR ₁₃)R ₁₂、-C _0-4-N(R ₁₃)-C(＝NR ₁₄)R ₁₂、-C _0-4-C(O)NR ₁₃R ₁₄or-C_0-4-N(R ₁₃)-C(O)R ₁₂Substituted with the substituent(s);

    R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄r is as defined in claim 1.
11. The compound of formula (I), its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof according to claim 10, wherein R is₈、R ₉Each independently selected from deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted with one or more moieties selected from deuteriumHalogen, cyano, C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocyclyl, C_5-8Aryl, 5-8 membered heteroaryl, ═ O, -O-R₁₁、-C(O)R ₁₂、-O-C(O)R ₁₂or-NR₁₃R ₁₄Is substituted with a substituent of (A), or, R₈、R ₉Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, said group being optionally further substituted by one or more groups selected from the group consisting of_1-4Alkyl, ═ O, -S (O)_rR ₁₀、-O-R ₁₁or-C (O) R₁₂Substituted with the substituent(s);

    R ₁₀、R ₁₁、R ₁₂、R ₁₃、R ₁₄r is as defined in claim 10.
12. The compound of formula (I), its stereoisomers, prodrugs or a pharmaceutically acceptable salt thereof according to claim 10, wherein said compound of formula (I) has the following structure (iiib):

    

    wherein the content of the first and second substances,

    R ₂selected from phenyl, 5-6 membered heteroaryl containing 1 or 2 nitrogen heteroatoms or-NR₁₃R ₁₄Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C_1-4Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, ═ O, hydroxy, methoxy, ethoxy, carboxy, amino, dimethylamino, or diethylamino, optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, cyclopropyl, or hydroxy;

    R ₅、R ₆each independently selected from hydrogen, deuterium, halogen, methyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy or isopropoxy, said groups optionally being further substituted by one or more substituents selected from deuterium, fluoro or cyclopropyl;

    R ₈、R ₉each independently selected from deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, ═ O, amino, dimethylamino, diethylamino or C_1-4Substituted with a substituent of alkanoyl or,

    R ₈、R ₉together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, methoxy, ethoxy, isopropoxy or C_1-4Substituted by alkanoyl group;

    R ₁₃、R ₁₄each independently selected from hydrogen, deuterium, C_1-4Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethyl, trifluoromethyl, dideuteromethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, triazole, amino, dimethylamino, diethylamino or C_1-4Substituted with a substituent of alkanoyl or,

    R ₁₃、R ₁₄together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, hydroxy, C_1-4Alkyl, difluoromethaneA group, trifluoromethyl, dideuterylmethyl, trideuteromethyl, methoxy, ethoxy, isopropoxy, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, morpholinyl, piperazinyl, amino, dimethylamino, diethylamino or C_1-4Substituted by alkanoyl group;

    each of said heterocyclic groups independently optionally contains 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.
13. A compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is selected from the group consisting of:

    

    

    

    
14. a process for the preparation of a compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13, comprising the steps of:

    

    alternatively, the first and second electrodes may be,

    

    alternatively, the first and second electrodes may be,

    

    alternatively, the first and second electrodes may be,

    

    wherein, X, R₁、R ₂、R ₃、R ₄、R ₅、R ₆As claimed in claim 1.
15. A pharmaceutical composition which comprises a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13, and a pharmaceutically acceptable carrier.
16. The use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13 in the manufacture of a medicament for the treatment of a tumour or cancer; preferably, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, large intestine cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelogenous leukemia, hodgkin lymphoma or non-hodgkin lymphoma, fahrenheit macroglobulinemia, hairy lymphoma, cellular lymphoma, burkitt lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
17. The use of a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 13 in the manufacture of a medicament for the treatment of myeloproliferative disorders, bone or chondrocyte disorders, hypophosphatemia.
18. The use according to claim 17, wherein the myeloproliferative disorder is selected from the group consisting of polycythemia, essential thrombocythemia, or essential myelofibrosis; said skeletal or chondrocyte disorder is selected from dysplasia, achondroplasia, dwarfism, lethal Teratocarcinosis (TD), Alpeller's syndrome, Kluyverson's syndrome, Jackson-Weiss syndrome, Beare-Stevenson dermatofret syndrome, Pfeiffer syndrome or cranial muscle atrophy syndrome; the hypophosphatemia is selected from X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets or ovarian malacia induced by tumors.
19. A compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for use as an FGFR inhibitor for the treatment of a disease associated with aberrant expression, mutation or aberrant expression and activity of FGFR receptors; preferably, they are useful as selective FGFR2 and/or FGFR3 inhibitors for the treatment of diseases associated with aberrant expression, mutation or aberrant expression and activity of FGFR2 or FGFR3 receptors.